Department of Pharmacy, Affiliated Cancer Hospital of Nantong University, Nantong, 226001, China.
Nantong Maternal and Children Health Care Service Hospital, Nantong, Jiangsu, 226018, China.
Biomed Pharmacother. 2018 Jan;97:1586-1594. doi: 10.1016/j.biopha.2017.11.117. Epub 2017 Nov 27.
Inflammation and oxidative stress are two crucial factors mediating liver fibrosis. Stachydrine (STA) is a naturally occurring compound extracted from a medicinal plant Leonuru heterophyllus, which can inhibit the proliferation and induce the apoptosis of breast cancer cells, relieve high glucose-induced endothelial cell senescence and isoproterenol-induced cardiac hypertrophy, and exert antitumor effects. However, its roles in hepatic fibrosis remain largely unknown. We aimed to evaluate the effect of STA on carbon tetrachloride (CCl)-induced hepatic fibrosis in rats and to elucidate the possible mechanisms. STA alleviated the pathological changes caused by CCl injection in livers compared to the normal liver. Hematoxylin-eosin staining further showed that STA treatment remarkably improved the liver histology, as evidenced by mitigated hepatic steatosis, necrosis, and fibrotic septa. STA reduced the liver/body weight ratio and the serum levels of aminotransferase, aspartate aminotransferase and alkaline phosphatase. It also significantly decreased collagen deposition and hydroxyproline level. Both mRNA and protein levels of α-SMA, α1(I)-procollagen and fibronectin were decreased by STA compared to those of the model group. STA significantly inhibited the expressions of inflammatory factors interleukin-6 (IL-6), IL-8, IL-1β, tumor necrosis factor-α, inducible nitric oxide synthase and cyclooxygenase-2. It suppressed oxidative stress by decreasing malondialdehyde level as well as increasing glutathione level and enzymatic activities of superoxide dismutase, catalase, glutathione reductase and glutathione peroxidase. STA also significantly increased the protein expressions of tissue inhibitor of metallopeptidase-1 (TIMP-1) and TIMP-2 but decreased those of matrix metalloproteinase-2 (MMP-2) and MMP-9, indicating excessive basement membrane in the fibrotic liver. Collectively, STA has potent protective effects on the liver, with therapeutic implication for liver fibrosis.
炎症和氧化应激是介导肝纤维化的两个关键因素。水苏碱（STA）是一种从益母草中提取的天然化合物，它可以抑制乳腺癌细胞的增殖并诱导其凋亡，减轻高葡萄糖诱导的内皮细胞衰老和异丙肾上腺素诱导的心肌肥厚，并发挥抗肿瘤作用。然而，其在肝纤维化中的作用在很大程度上尚不清楚。我们旨在评估 STA 对四氯化碳（CCl）诱导的大鼠肝纤维化的影响，并阐明可能的机制。与正常肝脏相比，STA 减轻了 CCl 注射引起的肝脏病变。苏木精-伊红染色进一步表明，STA 治疗显著改善了肝脏组织学，减轻了肝脂肪变性、坏死和纤维性隔室。STA 降低了肝/体重比和血清转氨酶、天冬氨酸转氨酶和碱性磷酸酶水平。它还显著减少了胶原沉积和羟脯氨酸水平。与模型组相比，STA 降低了α-SMA、α1（I）-原胶原和纤维连接蛋白的 mRNA 和蛋白水平。STA 显著抑制了炎症因子白细胞介素-6（IL-6）、IL-8、IL-1β、肿瘤坏死因子-α、诱导型一氧化氮合酶和环氧化酶-2 的表达。它通过降低丙二醛水平、增加谷胱甘肽水平以及超氧化物歧化酶、过氧化氢酶、谷胱甘肽还原酶和谷胱甘肽过氧化物酶的酶活性来抑制氧化应激。STA 还显著增加了组织金属蛋白酶抑制剂-1（TIMP-1）和 TIMP-2 的蛋白表达，但降低了基质金属蛋白酶-2（MMP-2）和 MMP-9 的蛋白表达，表明纤维化肝脏中存在过多的基底膜。总之，STA 对肝脏具有强大的保护作用，对肝纤维化具有治疗意义。
